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Sunday, August 14, 2022

Immunotherapy research aids in fight against cancer

Like an inoperable tumor inside a patient’s brain, cancer has rooted itself deep within our society. Unfortunately, the current treatments of cancer are almost as unpredictable as the disease itself. But what if the key to fighting this ominous disease has been waging war inside our bodies all along? That is the question put forth by the field of cancer immunotherapy, a cancer treatment that utilizes the body’s own immune system. It is the research topic for Kenneth DeSantes, pediatric oncologist and hematologist at the UW-Madison School of Medicine and Public Health.

“In the early 90s when I was starting, there was a lot of excitement originally generated about immunotherapy,” DeSantes said. Unfortunately, the excitement was somewhat premature.

“Like many things, when we got a little more experience with [immunotherapy], it didn’t work nearly as well as people hoped it would. The excitement died down and a lot of people thought that was it … But a few of us persisted,” DeSantes said. Because of DeSantes’ passion for helping children and their families, he turned his work towards immunotherapy for pediatric cancers.

Right now, three of the most exciting immune components fighting on our side are monoclonal antibodies, natural killer (NK) cells and chimeric antigen receptor (CAR) T-cells.

An antibody is like the sight on a weapon for the immune system. Antibodies target the immune system’s attack by recognizing a single molecule on the surface of the cell, called an antigen. The antibody then binds to the antigen, allowing the immune system to form a bridge between the immune cell and the antigen, which may be on a germ or a cancer cell. There are billions of different types of antigens. Many antigens appearing on tumor cells may also appear on healthy cells. There are very few antigens that are completely tumor-specific, so it’s necessary to create antibodies that target a tumor-specific antigen.

“There was a study that looked at patients with relapsed neuroblastoma (a deadly type of cancer seen almost exclusively in children) and it turned out that the patients who got the chemotherapy with the antibody had a very good response rate. Here, the antibody worked synergistically with the chemotherapy,” DeSantes said.

The antibody used in the trial targeted an antigen very specific to a neuroblastoma cell. This allowed the immune system to attack the malignant cells more effectively, while chemotherapy was also able to target the cancer. Using immunotherapy, current treatments like chemotherapy were improved.

DeSantes uses a compound called MIBG, which works similarly to antibodies. Radioactive iodine is attached to MIBG and incorporated into the cancer cell targets. MIBG is a huge aid in delivering radiation therapy to cancer cells and avoiding unnecessary irradiation of healthy cells. It is currently being used to treat children with neuroblastomas and adults with a different type of cancer known as pheochromocytoma.

Antibodies and MIBG help the immune cells already present in a patient’s body better attack cancer cells. An alternative method is transferring new immune cells from another person into the patient’s own supply, which can increase the force of the attack. One type of immune cell currently being transferred in this way is NK cells, which can recognize and attack cells that have become “stressed” because of infection or malignancy.

A major concern during an immune cell transfusion is that the patient’s body recognizes foreign antigens present on the new cells and destroys them before they have a chance to attack the cancer. A group of antigens called HLA determines what the immune system defines as ‘self’ and harmless, versus ‘non-self’ and harmful.

DeSantes will be opening a new trial based on this type of immunotherapy for children with neuroblastoma. They will be using parents as the donors of the NK cells because the parents’ HLA molecules will be around half identical to that of the patient’s, which could prolong the survival of the NK cells after infusion.

A concern with immunotherapy is that toxicity caused by the presence of antibodies may be a real threat to patients. Doctors aim to create a treatment that will have lasting benefits that are worth the immediate controllable toxicity. That is the idea behind CAR T-cells.

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“A single antibody has a limited lifespan, and it may cause some toxic or off target effects, but it will clear from the system quickly, and then it’s gone. It’s a very self-limiting therapy. The CAR T-cells are a living drug. They have a full life. After you infuse them, they can potentially live forever in the body. So the potential for severe toxicity is very real,” DeSantes said.

A regular T-cell is a cell that has an antibody bound to its surface. That part of the cell recognizes and joins together with an antigen on the target cell. The T-cell can then kill its target and send out signals to recruit other types of immune cells to the scene. The T-cell is a fighter and a diplomat, evaluating the threat and sending for backup when needed.

A CAR T-cell is a T-cell improved through gene editing. It’s still the diplomat, but it already knows which cells are dangerous and has equipment to create a more rapid and directed response to the threat.

DeSantes and his team are using a specific type of CAR T-cell to target cancer. These CAR T-cells appear to remain alive in the body long enough to create lasting results. Persistence of the cells in the patient is an important consideration for CAR T-cells in order to promote lasting remissions.

In many ways, it’s just the promising beginning of a field that DeSantes has been following throughout his career.

“Today, one of the most exciting breakthroughs against both pediatric and adult cancers is the application of immunotherapy,” DeSantes said.

As the war against cancer rages on, doctors like DeSantes help us gain an advantage against the disease. As we continue to learn more, research will be able to employ even more innovative strategies. It will be important for the future of cancer immunotherapy to maintain the ideals that DeSantes and his colleagues did years ago when immunotherapy was almost overlooked.

“It’s very gratifying to see how it’s turning out, because I never gave up on it,” DeSantes said.

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